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Thrombosis and Haemostasis Jul 2022The antiphospholipid syndrome is characterized by antibodies directed against phospholipid-binding proteins and phospholipids attached to cell membrane receptors,...
The antiphospholipid syndrome is characterized by antibodies directed against phospholipid-binding proteins and phospholipids attached to cell membrane receptors, mitochondria, oxidized lipoproteins, and activated complement components. When antibodies bind to these complex antigens, cells are activated and the coagulation and complement cascades are triggered, culminating in thrombotic events and pregnancy morbidity that further define the syndrome. The phospholipid-binding proteins most often involved are annexins II and V, β-glycoprotein I, prothrombin, and cardiolipin. A distinguishing feature of the antiphospholipid syndrome is the "lupus anticoagulant." This is not a single entity but rather a family of antibodies directed against complex antigens consisting of β-glycoprotein I and/or prothrombin bound to an anionic phospholipid. Although these antibodies prolong in vitro clotting times by competing with clotting factors for phospholipid binding sites, they are not associated with clinical bleeding. Rather, they are thrombogenic because they augment thrombin production in vivo by concentrating prothrombin on phospholipid surfaces. Other antiphospholipid antibodies decrease the clot-inhibitory properties of the endothelium and enhance platelet adherence and aggregation. Some are atherogenic because they increase lipid peroxidation by reducing paraoxonase activity, and others impair fetal nutrition by diminishing placental antithrombotic and fibrinolytic activity. This plethora of destructive autoantibodies is currently managed with immunomodulatory agents, but new approaches to treatment might include vaccines against specific autoantigens, blocking the antibodies generated by exposure to cytoplasmic DNA, and selective targeting of aberrant B-cells to reduce or eliminate autoantibody production.
Topics: Antiphospholipid Syndrome; Female; Humans; Lupus Coagulation Inhibitor; Phospholipids; Placenta; Pregnancy; Prothrombin; Thrombosis; beta 2-Glycoprotein I
PubMed: 34794200
DOI: 10.1055/a-1701-2809 -
ACS Chemical Biology Nov 2019Synthesis and regulation of lipid levels and identities is critical for a wide variety of cellular functions, including structural and morphological properties of... (Review)
Review
Synthesis and regulation of lipid levels and identities is critical for a wide variety of cellular functions, including structural and morphological properties of organelles, energy storage, signaling, and stability and function of membrane proteins. Proteolytic cleavage events regulate and/or influence some of these lipid metabolic processes and as a result help modulate their pleiotropic cellular functions. Proteins involved in lipid regulation are proteolytically cleaved for the purpose of their relocalization, processing, turnover, and quality control, among others. The scope of this review includes proteolytic events governing cellular lipid dynamics. After an initial discussion of the classic example of sterol regulatory element-binding proteins, our focus will shift to the mitochondrion, where a range of proteolytic events are critical for normal mitochondrial phospholipid metabolism and enforcing quality control therein. Recently, mitochondrial phospholipid metabolic pathways have been implicated as important for the proliferative capacity of cancers. Thus, the assorted proteases that regulate, monitor, or influence the activity of proteins that are important for phospholipid metabolism represent attractive targets to be manipulated for research purposes and clinical applications.
Topics: Animals; Cell Membrane; Cholesterol; Gene Expression Regulation; Humans; Lipid Metabolism; Mitochondria; Peptide Hydrolases; Phospholipids; Protein Binding; Protein Conformation; Proteolysis; Signal Transduction
PubMed: 31503446
DOI: 10.1021/acschembio.9b00695 -
Biochimica Et Biophysica Acta.... Jul 2022Adenosine triphosphate-binding cassette transporter subfamily A member 7 (ABCA7) performs incompletely understood biochemical functions that affect pathogenesis of...
Adenosine triphosphate-binding cassette transporter subfamily A member 7 (ABCA7) performs incompletely understood biochemical functions that affect pathogenesis of Alzheimer's disease. ABCA7 is most similar in primary structure to ABCA1, the protein that mediates cell lipid efflux and formation of high-density lipoprotein (HDL). Lipid metabolic labeling/tracer efflux assays were employed to investigate lipid efflux in BHK-ABCA7(low expression), BHK-ABCA7(high expression) and BHK-ABCA1 cells. Shotgun lipid mass spectrometry was used to determine lipid composition of HDL synthesized by BHK-ABCA7 and BHK-ABCA1 cells. BHK-ABCA7(low) cells exhibited significant efflux only of choline-phospholipid and phosphatidylinositol. BHK-ABCA7(high) cells had significant cholesterol and choline-phospholipid efflux to apolipoprotein (apo) A-I, apo E, the 18A peptide, HDL, plasma and cerebrospinal fluid and significant efflux of sphingosine-lipid, serine-lipid (which is composed of phosphatidylserine and phosphatidylethanolamine in BHK cells) and phosphatidylinositol to apo A-I. In efflux assays to apo A-I, after adjustment to choline-phospholipid, ABCA7-mediated efflux removed ~4 times more serine-lipid and phosphatidylinositol than ABCA1-mediated efflux, while ABCA1-mediated efflux removed ~3 times more cholesterol than ABCA7-mediated efflux. Shotgun lipidomic analysis revealed that ABCA7-HDL had ~20 mol% less phosphatidylcholine and 3-5 times more serine-lipid and phosphatidylinositol than ABCA1-HDL, while ABCA1-HDL contained only ~6 mol% (or ~1.1 times) more cholesterol than ABCA7-HDL. The discrepancy between the tracer efflux assays and shotgun lipidomics with respect to cholesterol may be explained by an underestimate of ABCA7-mediated cholesterol efflux in the former approach. Overall, these results suggest that ABCA7 lacks specificity for phosphatidylcholine and releases significantly but not dramatically less cholesterol in comparison with ABCA1.
Topics: ATP-Binding Cassette Transporters; Apolipoprotein A-I; Cholesterol; Choline; Lipoproteins, HDL; Phosphatidylcholines; Phosphatidylinositols; Phospholipids; Serine
PubMed: 35381375
DOI: 10.1016/j.bbalip.2022.159157 -
FEBS Letters Apr 2013Phospholipids (PLs), well known for their fundamental role in cellular structure, play critical signaling roles via their derivatives and cleavage products acting as... (Review)
Review
Phospholipids (PLs), well known for their fundamental role in cellular structure, play critical signaling roles via their derivatives and cleavage products acting as second messengers in signaling cascades. Recent work has shown that intact PLs act as signaling molecules in their own right by modulating the activity of nuclear hormone transcription factors responsible for tuning genes involved in metabolism, lipid flux, steroid synthesis and inflammation. As such, PLs have been classified as novel hormones. This review highlights recent work in PL-driven gene regulation with a focus on the unique structural features of phospholipid-sensing transcription factors and what sets them apart from well known soluble phospholipid transporters.
Topics: Gene Expression Regulation; Humans; Models, Genetic; Models, Molecular; Molecular Structure; Phospholipids; Protein Binding; Protein Structure, Tertiary; Signal Transduction; Transcription Factors
PubMed: 23333623
DOI: 10.1016/j.febslet.2013.01.004 -
Advances in Biological Regulation Jan 2018The phospholipase A superfamily of enzymes plays a significant role in the development and progression of numerous inflammatory diseases. Through their catalytic action... (Review)
Review
The phospholipase A superfamily of enzymes plays a significant role in the development and progression of numerous inflammatory diseases. Through their catalytic action on membrane phospholipids, phospholipases are the upstream regulators of the eicosanoid pathway releasing free fatty acids for cyclooxygenases, lipoxygenases, and cytochrome P450 enzymes which produce various well-known inflammatory mediators including leukotrienes, thromboxanes and prostaglandins. Elucidating the association of phospholipases A with the membrane, the extraction and binding of phospholipid substrates, and their interactions with small-molecule inhibitors is crucial for the development of new anti-inflammatory therapeutics. Studying phospholipases has been challenging because they act on the surface of cellular membranes and micelles. Multidisciplinary approaches including hydrogen/deuterium exchange mass spectrometry, molecular dynamics simulations, and other computer-aided drug design techniques have been successfully employed by our laboratory to study interactions of phospholipases with membranes, phospholipid substrates and inhibitors. This review summarizes the application of these techniques to study four human recombinant phospholipases A.
Topics: Cell Membrane; Deuterium Exchange Measurement; Humans; Mass Spectrometry; Molecular Dynamics Simulation; Phospholipases A2; Phospholipids
PubMed: 29248300
DOI: 10.1016/j.jbior.2017.10.009 -
Cell Chemical Biology Jul 2022Phospholipids are ligands for nuclear hormone receptors (NRs) that regulate transcriptional programs relevant to normal physiology and disease. Here, we demonstrate that...
Phospholipids are ligands for nuclear hormone receptors (NRs) that regulate transcriptional programs relevant to normal physiology and disease. Here, we demonstrate that mimicking phospholipid-NR interactions is a robust strategy to improve agonists of liver receptor homolog-1 (LRH-1), a therapeutic target for colitis. Conventional LRH-1 modulators only partially occupy the binding pocket, leaving vacant a region important for phospholipid binding and allostery. Therefore, we constructed a set of molecules with elements of natural phospholipids appended to a synthetic LRH-1 agonist. We show that the phospholipid-mimicking groups interact with the targeted residues in crystal structures and improve binding affinity, LRH-1 transcriptional activity, and conformational changes at a key allosteric site. The best phospholipid mimetic markedly improves colonic histopathology and disease-related weight loss in a murine T cell transfer model of colitis. This evidence of in vivo efficacy for an LRH-1 modulator in colitis represents a leap forward in agonist development.
Topics: Animals; Colitis; Ligands; Mice; Phospholipids; Receptors, Cytoplasmic and Nuclear
PubMed: 35316658
DOI: 10.1016/j.chembiol.2022.03.001 -
Advances in Biological Regulation Jan 2017Nuclear receptors are ligand-activated transcription factors whose diverse biological functions are classically regulated by cholesterol-based small molecules. Over the... (Review)
Review
Nuclear receptors are ligand-activated transcription factors whose diverse biological functions are classically regulated by cholesterol-based small molecules. Over the past few decades, a growing body of evidence has demonstrated that phospholipids and other similar amphipathic molecules can also specifically bind and functionally regulate the activity of certain nuclear receptors, suggesting a critical role for these non-cholesterol-based molecules in transcriptional regulation. Phosphatidylcholines, phosphoinositides and sphingolipids are a few of the many phospholipid like molecules shown to quite specifically regulate nuclear receptors in mouse models, cell lines and in vitro. More recent evidence has also shown that certain nuclear receptors can "present" a bound phospholipid headgroup to key lipid signaling enzymes, which can then modify the phospholipid headgroup with very unique kinetic properties. Here, we review the broad array of phospholipid/nuclear receptor interactions, from the perspective of the chemical nature of the phospholipid, and the cellular abundance of the phospholipid. We also view the data in the light of well established paradigms for phospholipid mediated transcriptional regulation, as well as newer models of how phospholipids might effect transcription in the acute regulation of complex nuclear signaling pathways. Thus, this review provides novel insight into the new, non-membrane associated roles nuclear phospholipids play in regulating complex nuclear events, centered on the nuclear receptor superfamily of transcription factors.
Topics: Animals; Gene Expression Regulation; Humans; Ligands; Mice; Models, Molecular; Phospholipids; Protein Binding; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Transcription Factors; Transcription, Genetic
PubMed: 27838257
DOI: 10.1016/j.jbior.2016.10.006 -
The Journal of Biological Chemistry Mar 2019Toll-like receptors (TLRs) coupled to intracellular signaling cascades function as central elements of innate immunity that control transcription of numerous... (Review)
Review
Toll-like receptors (TLRs) coupled to intracellular signaling cascades function as central elements of innate immunity that control transcription of numerous pro-inflammatory genes. Two minor anionic phospholipids present in the pulmonary surfactant complex, palmitoyl-oleoyl-phosphatidylglycerol (POPG) and phosphatidylinositol (PI), antagonize the cognate ligand activation of TLRs 2 and 4. The lipids block recognition of activating ligands by the TLRs, either directly or via the TLR4 coreceptors CD14 and MD2. Antagonism of TLR activation results in inhibition of the initiating step of the pro-inflammatory signaling pathways. Evidence for this mechanism of action comes from direct binding studies between CD14 and MD2 with POPG and PI. Additional evidence for this mechanism of antagonism also comes from monitoring the reduction of protein phosphorylation events that characterize the intracellular signaling by activated TLRs. The pathogenesis of respiratory syncytial virus (RSV) and influenza A virus (IAV) have been linked to TLR4 activation, and we examined the action of POPG and PI as potential antagonists of the pathology of these viruses. Surprisingly, POPG and PI dramatically curtail infection, in addition to inhibiting inflammatory sequelae associated with RSV and IAV infections. The mechanism of action by the lipids is disruption of virus particle binding to host cell plasma membrane receptors, required for viral uptake. The antagonism of activation of TLRs and virus binding to the alveolar epithelium by resident constituents of the pulmonary surfactant system suggests that POPG and PI function in homeostasis, to prevent inflammatory processes that result in reductions in gas exchange within the alveolar compartment.
Topics: Animals; Humans; Immunity, Innate; Influenza A virus; Phospholipids; Pulmonary Surfactants; Respiratory Syncytial Viruses; Respiratory Tract Infections
PubMed: 30733339
DOI: 10.1074/jbc.AW118.003229 -
The Journal of Physical Chemistry. B May 2023In this work, the influence of membrane curvature on the Ca binding to phospholipid bilayers is investigated by means of molecular dynamics simulations. In particular,...
In this work, the influence of membrane curvature on the Ca binding to phospholipid bilayers is investigated by means of molecular dynamics simulations. In particular, we compared Ca binding to flat, elastically buckled, or uniformly bent zwitterionic and anionic phospholipid bilayers. We demonstrate that Ca ions bind preferably to the concave membrane surfaces in both types of bilayers. We also show that the membrane curvature leads to pronounced changes in Ca binding including differences in free ion concentrations, lipid coordination distributions, and the patterns of ion binding to different chemical groups of lipids. Moreover, these effects differ substantially for the concave and convex membrane monolayers. Comparison between force fields with either full or scaled charges indicates that charge scaling results in reduction of the Ca binding to curved phosphatidylserine bilayers, while for phosphatidylcholine membranes, calcium binds only weakly for both force fields.
Topics: Phospholipids; Lipid Bilayers; Calcium; Molecular Dynamics Simulation; Phosphatidylcholines; Ions
PubMed: 37191140
DOI: 10.1021/acs.jpcb.3c01962 -
The Journal of Biological Chemistry May 2022Lipids play critical roles in several major chronic diseases of our times, including those that involve inflammatory sequelae such as metabolic syndrome including... (Review)
Review
Lipids play critical roles in several major chronic diseases of our times, including those that involve inflammatory sequelae such as metabolic syndrome including obesity, insulin sensitivity, and cardiovascular diseases. However, defining the substrate specificity of enzymes of lipid metabolism is a challenging task. For example, phospholipase A (PLA) enzymes constitute a superfamily of degradative, biosynthetic, and signaling enzymes that all act stereospecifically to hydrolyze and release the fatty acids of membrane phospholipids. This review focuses on how membranes interact allosterically with enzymes to regulate cell signaling and metabolic pathways leading to inflammation and other diseases. Our group has developed "substrate lipidomics" to quantify the substrate phospholipid specificity of each PLA and coupled this with molecular dynamics simulations to reveal that enzyme specificity is linked to specific hydrophobic binding subsites for membrane phospholipid substrates. We have also defined unexpected headgroup and acyl chain specificity for each of the major human PLA enzymes, which explains the observed specificity at a structural level. Finally, we discovered that a unique hydrophobic binding site-and not each enzyme's catalytic residues or polar headgroup binding site-predominantly determines enzyme specificity. We also discuss how PLAs release specific fatty acids after allosteric enzyme association with membranes and extraction of the phospholipid substrate, which can be blocked by stereospecific inhibitors. After decades of work, we can now correlate PLA specificity and inhibition potency with molecular structure and physiological function.
Topics: Allosteric Regulation; Fatty Acids; Humans; Phospholipases A2; Phospholipids; Substrate Specificity
PubMed: 35358512
DOI: 10.1016/j.jbc.2022.101873